Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck region; in the USA, over 45,000 cases and about 11,000 deaths from the disease occur annually. Progress in the prevention and control of OSCC has been hampered by the lack of appropriate animal models that would reflect human exposure. Tobacco smoking is considered a major etiological factor in the development of oral cancer. An attractive animal model would be one where tumors resulting from chronic exposure of the animal to chemical carcinogens present in cigarette smoke, would recapitulate the biochemical, molecular and cellular alterations observed in human OSCC during the development of the disease. We have developed such a model and propose to apply it to chemoprevention. Previous studies have demonstrated the ability of diets containing 5-10% freeze-dried black raspberry (BRB) powder to inhibit the development of chemically-induced cancers in multiple organ sites in rodents including the oral cavity. 7,12-Dimethylbenz(a)anthracene (DMBA) induced squamous cell carcinomas (SCC) in the hamster cheek pouch. However, DMBA is not present in the environment and the hamster cheek pouch model may not be applicable to humans. We have shown that the tobacco carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) can induce SCC in oral tissues. Its metabolite, ()-anti- DB[a,l]PDE is a potent and specific carcinogen in oral tissues in mice and the mutational profiles induced by DB[a,l]P and its diol epoxide are very similar, consistent with the formation of stable covalent DNA adducts (Preliminary Results). Mutations in both lacI and p53 genes in oral tissues of mice treated with DB[a,l]P are similar to those observed in OSCC in humans. In addition, DNA lesions induced by DB[a,l]P and ()-anti- DB[a,l]PDE in the oral tissues of mice were detected by LC-MS/MS. Preliminary Results showed 5% BRB powder or 0.025% kaempferol (KF) in diets significantly inhibited DB[a,l]P-DNA adduct formation in the oral cavity of mice treated with DB[a,l]P. We hypothesize that BRB and its active components including BRB powder and its anthocyanins enriched extract, protocatechuic acid (a major metabolite of anthocyanins), KF, and ferulic acid (components of raspberries) will inhibit oral tumorigenesis and do so by multiple mechanisms including: inhibition of DNA damage and cell proliferation, modulation of genes critical to cancer progression, and induction of apoptosis (Aim 1), and will also exhibit the same mechanistic effects in human oral cell cultures representing different stages of the disease (Aim 2). Aim 2 will extend and translate our findings to future clinical studies. Innovation: This application is he first to examine the chemopreventive effects of BRB and related agents on the induction of OSCC in a highly relevant animal model. The mechanisms of chemoprevention by BRB will also be investigated. Relevance/Impact: The results of this study using a relevant animal model for OSCC will provide mechanistic insights that are urgently needed to formulate the most effective strategies for future clinical chemoprevention trials by BRB and its active compounds.